EP3 receptor-mediated contraction of human pulmonary arteries and inhibition of neurogenic tachycardia in pithed rats

Abstract

BackgroundThe aim of our study was (1) the pharmacological characterization of EP3 receptors in human pulmonary arteries and (2) the examination of the potential involvement of these receptors in the regulation of neurogenic tachycardia in pithed rats. L-826266 served as the EP3 receptor antagonist. MethodsExperiments were performed on isolated human pulmonary arteries and pithed rats. ResultsThe prostanoid EP1/EP3 receptor agonist sulprostone (1nM – 100μM) concentration-dependently contracted isolated human pulmonary arteries (pEC50, 6.88±0.10). The EP1 receptor antagonist SC 19920 (100μM) did not affect the vasoconstriction induced by sulprostone, the TP receptor antagonist sulotroban (10μM) only slightly attenuated the effects elicited by sulprostone >3μM, whereas L-826266 (10μM) shifted its concentration-response curve to the right (apparent pA2 value 6.18; incubation time 0.5h). In rings exposed to L-826266 (0.1,1 or 10μM) for 3h, a concentration-dependent inhibitory effect against the sulprostone-induced vasoconstriction was obtained, yielding a Schild plot-based pA2 value of 7.39. In pithed rats, sulprostone (10 – 1,000nmol/kg), but not the IP/EP1 receptor agonist iloprost (1-100nmol/kg), inhibited the electrically evoked increase in heart rate (HR) dosedependently, maximally by at least 80%. L-826266 (3μmol/kg) did not affect basal HR and diastolic blood pressure, but reduced the inhibitory effect of sulprostone 1,000nmol/kg by about 20%. ConclusionEP3 receptors (1) located postsynaptically strongly contract human pulmonary arteries and (2) located presynaptically on sympathetic nerve fibers supplying the heart of pithed rats strongly inhibit the neurogenic tachycardia.